Urothelial ATP Signaling and Diabetic Bladder Dysfunction

尿路上皮 ATP 信号转导和糖尿病性膀胱功能障碍

• 批准号: 8069339
• 负责人: SYLVIA OTTILIE SUADICANI
• 金额: $ 28.47万
• 依托单位: ALBERT EINSTEIN COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-05-01 至 2014-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8069339
• 关键词: Animals; Biochemistry; Bladder; Bladder Diseases; Bladder Dysfunction; Bladder Urothelium; Communication; Development; Diabetes Mellitus; Dinoprostone; Fiber; Goals; Health; Image; In Vitro; Lead; Mediating; Membrane; Micturition Reflex; Molecular Biology; Motor; Myofibroblast; Nerve Fibers; Pathway interactions; Pharmacology; Physiology; Play; Prostaglandins; Proteins; Purinoceptor; Relative (related person); Role; Sensory; Signal Pathway; Signal Transduction; Signaling Molecule; Smooth Muscle; Smooth Muscle Myocytes; Streptozocin; Symptoms; System; Testing; Up-Regulation; Urodynamics; Urothelial Cell; Urothelium; afferent nerve; base; design; detrusor muscle; diabetic; diabetic rat; intercellular communication; new therapeutic target; novel; receptor; research study; response

DESCRIPTION (provided by applicant): ATP plays important roles in the sensory and motor functions of the urinary bladder. ATP released from parasympathetic fibers can excite the detrusor muscle, and ATP released from the urothelium in response to bladder distension can indirectly modulate detrusor contractility by activating afferent fibers, stimulating suburothelial myofibroblasts and inducing release of other signaling molecules from the urothelium. Pathological conditions can increase the purinergic component of the neurogenic detrusor contraction and also augment urothelial ATP release. In diabetes various urodynamic abnormalities can develop, including increased bladder activity. We have proposed that increased sensitivity of diabetic bladders to purinergic stimulation was related to upregulation of specific purinergic receptor (P2R) subtypes in the detrusor muscle, and that amplification of ATP signaling would directly contribute to the development of bladder overactivity in diabetes. Based on recent findings we have now evidence that ATP signaling in also amplified in the diabetic bladder urothelium. Expression of P2Rs, particularly the P2X7R and P2X3R subtypes, is markedly increased in the urothelium of STZ-diabetic rat bladders and responses to ATP are higher in STZ-diabetic urothelial cells. These findings combined with demonstrations that P2X7R activation can induce release of both ATP and prostaglandin (PGE2), suggest that not only the sensitivity to ATP but also ATP and PGE2 release from urothelial cells is increased in diabetic bladders. In this context, afferent signaling from the bladder as well as ability of urothelial cells, suburothelial myofibroblast and smooth muscle cells to communicate would be significantly enhanced and likely contribute to increase bladder activity in diabetes. To test the hypotheses that diabetes increases urothelial ATP signaling and communication between bladder compartments, and that enhanced ATP signaling within and from the bladder contributes to the development of bladder dysfunction in diabetes we will use a combination of molecular biology, biochemistry, pharmacology, in vitro subcellular imaging and whole animal physiology approaches. These studies are expected to lead to novel understanding of the interplay among specific membrane receptors and channel proteins involved in intercellular signaling between urothelium and bladder smooth muscle, and reveal novel therapeutic targets and strategies to ameliorate the symptoms of bladder dysfunction in diabetes. PUBLIC HEALTH RELEVANCE: The studies proposed in this RO1 application are expected to further our understanding of the interactions between the bladder urothelial, suburothelial and smooth muscle compartments and of how changes in the expression of main components of the urothelial ATP signaling contribute to the development of bladder dysfunction in diabetes.

描述（由申请人提供）：ATP在膀胱的感觉和运动功能中起着重要作用。从副交感纤维释放的ATP可以激发逼尿肌的肌肉，而从尿路上皮释放的ATP响应膀胱延伸可以通过激活传入的纤维，刺激阳离子肌纤维纤维细胞并释放其他信号分子从尿素中释放。病理条件可以增加神经源性迫害者收缩的嘌呤能成分，并增加尿路上皮ATP的释放。在糖尿病中，各种尿动力学异常可以发展，包括增加膀胱活性。我们已经提出，糖尿病性膀胱对嘌呤能刺激的敏感性提高与特异性嘌呤能受体（P2R）亚型的上调有关，而ATP信号传导的扩增将直接导致糖尿病中膀胱过度活跃的发展。根据最近的发现，我们现在有证据表明，ATP信号在糖尿病膀胱尿皮上也得到了扩增。在STZ-糖尿病大鼠膀胱的尿皮细胞中，P2RS的表达，尤其是P2X7R和P2X3R亚型的表达明显增加，并且在STZ糖尿病尿路上皮细胞中对ATP的反应更高。这些发现结合了证明P2X7R激活可以诱导ATP和前列腺素蛋白的释放（PGE2），这表明糖尿病性膀胱中不仅对尿皮细胞的敏感性，而且从尿路上皮细胞中释放ATP和PGE2的敏感性也会增加。在这种情况下，来自膀胱的传入信号以及尿路上皮细胞，层肌纤维细胞和平滑肌细胞的能力将显着增强，并可能有助于增加糖尿病的膀胱活性。为了测试糖尿病增加尿路上皮ATP信号传导和膀胱隔室之间的通信的假设，并增强了膀胱内外的ATP信号传导有助于糖尿病中膀胱功能障碍的发展，我们将使用分子生物学，生物化学，药理学，药理学，体内生物学和整个动物的组合。预计这些研究将导致对特定膜受体之间的相互作用的新了解，以及涉及尿路上皮和膀胱平滑肌之间细胞间信号传导的通道蛋白，并揭示了新的治疗靶标和策略，以改善糖尿病中膀胱功能障碍的症状。公共卫生相关性：预计在此RO1应用中提出的研究将进一步了解我们对膀胱尿层，层和平滑肌隔室之间的相互作用，以及尿路上皮ATP信号传导主要成分表达的变化如何有助于Daibetes膀胱功能障碍的发展。